Multiple Myeloma (MM) is the second most frequent hematological cancer in the US after non- Hodgkin's lymphoma with about 20,000 individuals succumbing to this dreaded disease each year in the US alone. Despite recent advances in its treatment, the median survival remains at 6 years, with only 10% of patients surviving at 10 years. Therefore there is an urgent need for new and effective therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, and shared across different MM subtypes. Our laboratory has devoted significant effort towards the identification of the molecular genetic events in this malignancy, with the goals of improving early detection and providing new molecular targets for the development of more effective therapies for this cancer. Preliminary data: In our previous studies we have documented that the Wnt/B-catenin/BCL9 pathway is one of such pathway involved in MM disease progression and maintenance. Specifically we have found that: i) BCL9 is overexpressed in most MM cells but it is not expressed in the normal cellular counterpart where they originate, ii) BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic and angiogenic properties to myeloma cells, iii) RNAi suppressed expression of either 2-catenin or BCL9 inhibits MM tumor growth in vitro and in vivo, and iv) stapled peptides of the BCL9 HD2 domain inhibit 2-catenin/BCL9-dependent transcriptional activity in MM cells. Working hypothesis: The 2-catenin/BCL9 transcriptional complex itself and some of the downstream transcriptional targets are novel important therapeutic targets in MM. Goals: Our goals are to validate and functionally characterize novel B-catenin/BCL9 transcriptional target genes and to explore the possible role of the 2-catenin/BCL9 protein complex itself as therapeutic target in MM. Experimental tools: To test our hypothesis we will use as tools stabilized alpha-helices of BCL9 to disrupt B-catenin/BCL9 protein interaction and stabilized nano particles to deliver BCL9 small interfering RNAs to myeloma cells. In addition, we will use our expertise with lentiviral-based gene transfer technologies for functional validation, using gain- and loss-of-function approaches as well as well-established in vitro and in vivo model systems that reflect the heterotopic interactions between the MM cell and bone marrow microenvironment. Expected results: i) to identify and validate novel downstream B-catenin/BCL9 downstream genes which could be used as therapeutic targets in MM, ii) to functionally characterize and validate the role of the B-catenin/BCL9 transcriptional complex itself as a novel therapeutic target in MM. Probable implications to Medicine: The potential implications are: i) to find novel genes involved in the pathogenesis and progression of MM, ii) to find novel molecular targets to effectively treat MM, and iii) to develop preclinical models for designing and assessing target-based therapeutic approaches in MM and other hematologic malignancies associated with dysregulated Wnt activity. PUBLIC HEALTH RELEVANCE: Multiple Myeloma (MM) is the second most frequent hematological cancer in the US after non-Hodgkin's lymphoma with about 20,000 individuals succumbing to this dreaded disease each year in the US alone. MM primarily affects older adults and it is more common in black populations than in Caucasians. Despite high- dose chemotherapy with stem cell support, MM remains incurable. Therefore, there is a significant need for continual efforts directed towards the development of novel and effective rational-based therapeutics for MM. Here, we propose to functionally characterize and validate as therapeutic target the BCL9 oncogene, a recently discovered transcriptional regulator protein that we have found to play important roles in the pathogenesis and progression of MM and colon carcinoma. The studies proposed in this RO1 are significant to Public Health in that they may lead to the development of novel pharmacologic strategies to treat MM and other cancers associated with deregulated Wnt signaling.